The Zapotecs and Mixtecs are the most numerous indigenous groups in Oaxaca, and theirs were also the largest settlements in the area before the Spanish conquest. Like the best of neighbors, their relations were at times strained, amicable, and often a bit of both. As Zaachila was considered the capital of the Zapotecs during the Classical period in the 13th century, the city shows perhaps a stronger mix of these two cultures.

Cosijoeza (also known as Cocijoeza or Cosiioeza), the penultimate Zapotec ruler before arrival of the Spanish, lived in Zaachila when the Zapotec empire was attacked by the Aztecs, lead by Ahuitzotl. With help from the Mixtec lead by Dzahuindanda, Zaachila was able to repel the Aztec offensive.

A second attack in the late 15th century was more successful. A truce was only achieved once Cocijoeza agreed to marry Ahuitzotl's daughter, known as Xilabela in Zapotec and Coyolicatzin in Náhuatl. Cocijoeza and Xilabela were the parents of Princess Donají and Cocijopii, the last Zapotec ruler. With this, the importance of the Zaachila lineage to Oaxacan history cannot be overstated.

Following Cocijopii's contact with the Spanish and eventual baptism and conversion into Catholicism in the 16h century, Zaachila was slowly abandoned by the Zapotecs and became buried and overgrown. Archeological works on this site were lead in 1962 by Roberto Gallego Ruiz. The majority of the structures explored were tombs. While many of the artifacts found within were moved to museums in Mexico City, Oaxaca, and abroad, the halls of the tombs are now open for exploration in Zaachila itself.

They are notable for the many figures on their walls. Some feature the geometric patterns typical of Mixtec-Zapotec sites like Mitla. Another shows an owl, considered the emblem of Zaachila. Perhaps the best-known however, is that of a Zapotec ruler in a flight-like position.